This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. The objective of this study project is to test the hypothesis that short hairpin RNA (shRNA) and micro (RNA) constructs delivered to the brain by viral vectors will be efficacious in decreasing mutant gene expression and improving motor function in rodent models of Huntington's disease (HD). HD is a neurodegenerative brain disease that is caused by a trinucleotide (CAG) repeat expansion in the IT locus on chromosome 4. The resulting mutant protein contains a polyglutamine stretch at the N terminus of the protein. HD is characterized by cell death throughout the brain, with the cortex and striatum exhibiting the largest amount of degeneration. Patients experience severe motor dysfunction, cognitive decline and psychiatric disturbances and normally die within 10-15 years of disease onset (usually in the fourth decade of life). Currently, there is no cure for HD and treatments aim at alleviating the symptoms of the disease, rather than preventing its development. RNA interference (RNAi) is a phenomenon naturally occurring in cells to regulate gene expression and scientists have co-opted this biological mechanism as a means by which to decrease the expression of disease-related genes. Our lab has previously identified several shRNAs and miRNAs that bind to mutant huntingtin (htt) and reduce its expression by approximately 50-60% upon expression in the mouse striatum. The goal of the current studies are to investigate whether this approach will be efficacious in long-term knockdown of htt and whether this treatment can prevent the development of behavioral deficits in a mouse model of HD.